Diabeta® product monograph - Sanofi Canada
Diabeta® product monograph - Sanofi Canada
Diabeta® product monograph - Sanofi Canada
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PRODUCT MONOGRAPH<br />
Pr DIAßETA ®<br />
Glyburide<br />
Manufacturer’s Standard<br />
2.5 and 5 mg Tablets<br />
Oral Hypoglycemic - Sulfonylurea<br />
sanofi-aventis <strong>Canada</strong> Inc.<br />
2905 Place Louis-R.-Renaud<br />
Laval, Quebec<br />
H7V 0A3<br />
Date of Revision:<br />
March 12, 2013<br />
Submission Control No.: 160736 s-a Version 4.0 dated March 12, 2013<br />
Page 1 of 26
Table of Contents<br />
PART I: HEALTH PROFESSIONAL INFORMATION ........................................................... 3<br />
SUMMARY PRODUCT INFORMATION ......................................................................... 3<br />
INDICATIONS AND CLINICAL USE ............................................................................... 3<br />
CONTRAINDICATIONS .................................................................................................... 3<br />
WARNINGS AND PRECAUTIONS ................................................................................... 4<br />
ADVERSE REACTIONS ..................................................................................................... 8<br />
DRUG INTERACTIONS ..................................................................................................... 9<br />
DOSAGE AND ADMINISTRATION ............................................................................... 15<br />
OVERDOSAGE ................................................................................................................. 16<br />
ACTION AND CLINICAL PHARMACOLOGY ............................................................. 17<br />
STORAGE AND STABILITY ........................................................................................... 18<br />
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................. 18<br />
PART II: SCIENTIFIC INFORMATION ................................................................................. 19<br />
PHARMACEUTICAL INFORMATION ........................................................................... 19<br />
CLINICAL TRIALS ........................................................................................................... 20<br />
DETAILED PHARMACOLOGY ...................................................................................... 20<br />
TOXICOLOGY .................................................................................................................. 20<br />
REFERENCES ................................................................................................................... 22<br />
PART III: CONSUMER INFORMATION ................................................................................ 24<br />
Page 2 of 26
PRODUCT MONOGRAPH<br />
Pr DIAßETA ®<br />
Glyburide<br />
Oral Hypoglycemic – Sulfonylurea<br />
PART I: HEALTH PROFESSIONAL INFORMATION<br />
SUMMARY PRODUCT INFORMATION<br />
Route of<br />
Administration<br />
Dosage Form /<br />
Strength<br />
Clinically Relevant Nonmedicinal<br />
Ingredients<br />
Oral Tablet 2.5 mg, 5 mg Lactose monohydrate<br />
For a complete listing see Dosage Forms,<br />
Composition and Packaging section.<br />
INDICATIONS AND CLINICAL USE<br />
DIAβETA (glyburide) is indicated as an adjunct to proper dietary management, exercise and<br />
weight reduction to lower blood glucose in adult patients with type 2 diabetes whose<br />
hyperglycemia cannot be controlled by diet and exercise alone or when insulin therapy is not<br />
required.<br />
Pediatrics (
Patients with Type 1 diabetes (formerly known as insulin-dependent diabetes<br />
mellitus or IDDM).<br />
Diabetic ketoacidosis with or without coma. This condition should be treated with<br />
insulin.<br />
Diabetic precoma or coma.<br />
During stress conditions such as severe infections, trauma or surgery.<br />
In the presence of liver disease or frank jaundice; or renal impairment.<br />
Patients treated with bosentan.<br />
Pregnancy and lactation.<br />
During pregnancy, no oral antidiabetic agent should be given.<br />
Due to the possible excretion in human milk, the patient should discontinue nursing<br />
or discontinue taking the drug depending on the importance of the drug to the<br />
mother. If glyburide is discontinued, the patient should be transferred to insulin<br />
therapy.<br />
WARNINGS AND PRECAUTIONS<br />
General<br />
Use of DIAβETA must be viewed by both the physician and patient as a treatment in<br />
addition to diet and exercise and not as a substitute for proper dietary management,<br />
exercise and weight reduction or as a convenient mechanism for avoiding dietary<br />
restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be<br />
transient, thus requiring only short-term administration of DIAβETA. As is necessary<br />
during treatment with any blood-glucose-lowering drug, the patient and the physician<br />
must be aware of the risk of hypoglycemia.<br />
In initiating treatment for type 2 diabetes, non-pharmacologic therapy (proper dietary<br />
management, exercise and weight reduction) should be emphasized as the initial form of<br />
treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient.<br />
Proper dietary management and exercise alone may be effective in controlling the blood glucose<br />
and symptoms of hyperglycemia. If non-pharmacologic therapy fails to reduce symptoms and/or<br />
blood glucose, the use of an oral sulfonylurea should be considered.<br />
Patient Selection and Follow-Up<br />
Careful selection of patients is important. It is recommended that response to sulfonylurea be<br />
measured as increased C-peptide. Those patients who do not respond with increased C-peptide<br />
will be less likely to show improvement.<br />
Page 4 of 26
It is imperative that there be careful ongoing attention to diet, adherence to regular exercise,<br />
reduction of body weight in obese patients, careful adjustment of dosage, instruction of the<br />
patient on hypoglycemic reactions and their control as well as regular, thorough follow-up<br />
examinations. Cardiovascular risk factors should be identified.<br />
The effectiveness of any oral hypoglycemic drug, including DIAβETA, in lowering blood<br />
glucose to a desired level decreases in many patients over a period of time, which may be due to<br />
progression of the severity of the diabetes or to diminished responsiveness to the drug. This<br />
phenomenon, known as secondary failure, is distinctive of primary failure in which the drug is<br />
ineffective in an individual patient when given for the first time.<br />
Patients should therefore be monitored with regular clinical and laboratory evaluations, including<br />
blood glucose and glycosylated hemoglobin (A1 C ) determinations, to determine the minimum<br />
effective dosage and to detect primary failure (inadequate lowering of blood glucose<br />
concentrations at the maximum recommended dosage) or secondary failure (progressive<br />
deterioration in blood sugar control following an initial period of effectiveness). The rate of<br />
primary failure will vary greatly depending upon patient selection and adherence to diet and<br />
exercise. The etiology of secondary failure is multifactorial and may involve progressive β-cell<br />
failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis<br />
to the sulfonylurea.<br />
Cardiovascular<br />
Some literature studies have suggested an association between the use of sulfonylureas and the<br />
risk of cardiovascular adverse events including cardiovascular mortality, since these agents may<br />
potentially impair cardioprotective processes. Although, there is inconsistency in the literature<br />
regarding a definite conclusion for this association, a cautious approach is nevertheless<br />
warranted. All patients on sulfonylureas, particularly high risk patients with cardiovascular<br />
disease, should be closely monitored for cardiovascular complications.<br />
Endocrine and Metabolism<br />
Loss of control of blood glucose<br />
If loss of adequate blood glucose lowering response to sulfonylurea is detected, treatment must<br />
be reassessed.<br />
When a patient stabilized on any diabetic regimen is exposed to stress such as illness during<br />
therapy, fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times,<br />
it may be necessary to adjust the dosage of DIAβETA or consider discontinuation of DIAβETA<br />
and administration of insulin.<br />
Hypoglycemia<br />
Hypoglycemia, sometimes prolonged and even life-threatening, may occur as a result of the<br />
blood-glucose-lowering action of DIAβETA. Proper patient selection, dosage, and instructions<br />
are important to avoid hypoglycemic episodes.<br />
Page 5 of 26
Hepatic and/or renal disease, inadequate caloric intake, malnutrition and/or irregular meals,<br />
exercise without adequate caloric supplementation, debility, advanced age, patient noncompliance,<br />
when alcohol is ingested, certain disorders of thyroid function, adrenal or pituitary<br />
insufficiency, excessive DIAβETA dosage, treatment with DIAβETA in the absence of<br />
indication or concurrent use with other agents with blood glucose lowering potential (see DRUG<br />
INTERACTIONS, Drug-Drug Interactions) may be predisposing factors. Oral hypoglycemic<br />
agents should be administered with caution to patients with Addison's disease. If such risk<br />
factors for hypoglycemia are present, it may be necessary to adjust the dosage of DIAβETA or<br />
the entire diabetes therapy. This also applies whenever illness occurs during therapy or the<br />
patient’s life style changes (see DOSAGE and ADMINISTRATION).<br />
The manifestations of hypoglycemia include: flushing or pallor, chilliness, excessive hunger,<br />
trembling, headache, dizziness, nausea, vomiting, restlessness, aggressiveness, depression,<br />
speech disorders, aphasia, sensory and/or visual disturbances, helplessness, lassitude, shallow<br />
respiration or bradycardia. In more severe cases, the clinical symptoms of a stroke or coma<br />
appear. However, symptoms of hypoglycemia are not necessarily as typical as described above<br />
and sulphonylureas may cause insidious development of symptoms mimicking cerebrovascular<br />
insufficiency (e.g. disordered sleep, somnolence, impaired alertness and reactions, confusion,<br />
delirium, cerebral convulsions, paralytic symptoms or loss of consciousness).<br />
Signs of adrenergic counter-regulation to hypoglycemia include: sweating, damp skin, anxiety,<br />
tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias. However, these<br />
symptoms may be milder or absent in patients who develop hypoglycemia gradually, patients<br />
with autonomic neuropathy, elderly or patients who receive concurrent treatment with<br />
sympatholytic agents (e.g. beta blockers, clonidine, reserpine, guanethidine) (see Drug-Drug<br />
Interactions).<br />
Mild to moderate episodes of hypoglycemia can usually be treated with oral carbohydrates.<br />
Artificial sweeteners are ineffective in controlling hypoglycemia. The symptoms of<br />
hypoglycemia nearly always subside when hypoglycemia is corrected.<br />
Despite initially successful countermeasures, hypoglycemia may recur. Patients must therefore<br />
remain under close observation.<br />
Severe hypoglycemia, which may be prolonged and has occasionally been life-threatening, may<br />
occur and mimics acute CNS disorders. Signs of severe hypoglycemia can include disorientation,<br />
loss of consciousness, and seizures. Severe hypoglycemia, or a protracted episode, which can<br />
only be temporarily controlled by usual amounts of sugar requires in-patient hospital care.<br />
Hematologic<br />
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency with<br />
sulfonylurea agents can lead to hemolytic anemia. Since DIAβETA belongs to the class of<br />
sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a<br />
nonsulfonylurea alternative should be considered.<br />
Page 6 of 26
Hepatic<br />
The metabolism and excretion of sulfonylureas including DIAβETA may be slowed in patients<br />
with impaired hepatic function (see Monitoring and Laboratory Tests below).<br />
Immune<br />
Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glyburide<br />
(see CONTRAINDICATIONS).<br />
Renal<br />
In patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage<br />
should be conservative to avoid hypoglycemic reactions.<br />
Special Populations<br />
Pregnant Women:<br />
The use of DIAβETA is contraindicated during pregnancy or for women planning a<br />
pregnancy (see CONTRAINDICATIONS). Recent information suggests that abnormal<br />
blood glucose levels during pregnancy are associated with a higher incidence of<br />
congenital abnormalities. Experts, including the Canadian Diabetes Association and the<br />
Canadian Medical Association recommend that insulin be used during pregnancy to<br />
maintain glucose levels as close to normal as possible.<br />
Nursing women:<br />
The use of DIAβETA is contraindicated in lactating women (see CONTRAINDICATIONS).<br />
Pediatrics:<br />
Safety and effectiveness of DIAβETA has not been established. Use in patients under 18 years of<br />
age is not recommended.<br />
Geriatrics:<br />
Elderly patients with type 2 diabetes are more susceptible to hypoglycemia.<br />
Monitoring and Laboratory Tests<br />
Fasting blood glucose should be monitored periodically to determine therapeutic response.<br />
Glycosylated hemoglobin (HbA 1C ) should also be monitored, usually every 3 to 6 months, to<br />
more precisely assess long-term glycemic control.<br />
Hepatic function should be assessed before initiating therapy and periodically in patients with<br />
impaired hepatic function.<br />
In patients with impaired renal function, blood and urine glucose should be regularly monitored.<br />
Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require<br />
periodic monitoring and special care.<br />
Periodic assessment of cardiovascular, ophthalmic, hematologic, renal and hepatic status is<br />
recommended.<br />
Page 7 of 26
ADVERSE REACTIONS<br />
Adverse Drug Reaction Overview<br />
The most commonly occurring significant adverse event of sulfonylureas (including<br />
DIAβETA) is hypoglycemia.<br />
The following serious adverse reactions have been reported with DIAβETA:<br />
Cases of severe hypoglycemia that may be prolonged and even life-threatening (see<br />
WARNINGS AND PRECAUTIONS).<br />
Impaired liver function (e.g. cholestasis and jaundice) and hepatitis which can lead to<br />
life-threatening liver failure (isolated cases).<br />
Serious and life-threatening sensitivity reactions including dyspnea, hypotension or shock<br />
(very rare).<br />
Potentially life-threatening cases of thrombocytopenia, leukopenia, agranulocytosis,<br />
pancytopenia, erythrocytopenia, granulocytopenia, hemolytic anemia and aplastic anemia (very<br />
rare).<br />
Clinical Trial Adverse Drug Reactions<br />
Because clinical trials are conducted under very specific conditions the adverse reaction<br />
rates observed in the clinical trials may not reflect the rates observed in practice and<br />
should not be compared to the rates in the clinical trials of another drug. Adverse drug<br />
reaction information from clinical trials is useful for identifying drug-related adverse<br />
events and for approximating rates.<br />
Less Common Clinical Trial Adverse Drug Reactions (
suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of<br />
ADH and/or increased release of ADH.<br />
Gastrointestinal:<br />
Nausea, epigastric fullness and heartburn are common reactions. Vomiting, diarrhea, and<br />
abdominal pain have also been reported. These tend to be dose related and may disappear<br />
when dosage is reduced.<br />
Hematologic:<br />
Potentially life-threatening changes in the blood picture may occur. Rare cases of mild to severe<br />
thrombocytopenia which can manifest itself as purpura have been reported. Leukopenia,<br />
agranulocytosis, pancytopenia (which may be due to myelosuppression), erythrocytopenia,<br />
granulocytopenia, hemolytic anemia and aplastic anemia have been observed very rarely with<br />
DIAβETA therapy. These reactions may be reversible following discontinuation of the<br />
sulfonylurea antidiabetic agent.<br />
Sensitivity/Resistance:<br />
Allergic and pseudoallergic skin reactions such as pruritus, erythema, rashes, urticaria,<br />
morbilliform or maculopapular eruptions have been reported in a number of patients. These may<br />
subside on continued use of DIAβETA, but if they persist the drug should be discontinued. Mild<br />
reactions such as urticaria may very rarely develop into serious and life-threatening reactions<br />
including dyspnea, hypotension or shock. In the event of urticaria, a physician must therefore be<br />
notified immediately. Porphyria cutanea tarda and photosensitivity reactions have been<br />
associated with the use of oral hypoglycemic drugs. Allergic vasculitis has been observed very<br />
rarely in patients receiving DIAβETA and in some circumstances may be life-threatening.<br />
Cross-sensitivity to sulfonamides or their derivatives may occur in patients treated with oral<br />
sulfonylurea hypoglycemic agents (see CONTRAINDICATIONS).<br />
Other:<br />
Transient visual disturbances may occur at the commencement of treatment due to fluctuations in<br />
blood glucose levels.<br />
DRUG INTERACTIONS<br />
Overview<br />
Weakening of the blood-glucose-lowering effect and, thus, raised blood glucose levels or<br />
potentiation of the blood-glucose lowering effect and thus hypoglycemia may occur when taking<br />
other drugs.<br />
DIAβETA is mainly metabolized by CYP2C9 and by CYP3A4. This should be taken into<br />
account when DIAβETA is co-administered with inducers or inhibitors of CYP2C9 and<br />
CYP3A4. Genetic polymorphisms of CYP2C9 may decrease oral clearance of DIABETA (see<br />
ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).<br />
Page 9 of 26
Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering<br />
action of DIAβETA in an unpredictable fashion. Intolerance to alcohol (disulfiram-like reaction:<br />
flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia) may occur in<br />
patients treated with oral hypoglycemic drugs. These reactions can be prevented by avoiding the<br />
use of alcohol.<br />
Page 10 of 26
Drug-Drug Interactions<br />
Patients who receive or discontinue certain medications while undergoing treatment with<br />
DIAβETA may experience changes in blood glucose control.<br />
Table 1. Drugs that may potentiate the hypoglycemic action<br />
Proper name Reference Effect Clinical comment<br />
ACE-inhibitors T The hypoglycemic action of When these drugs are<br />
Anabolic steroids and T<br />
sulfonylureas may be administered to a patient<br />
androgens<br />
potentiated.<br />
receiving DIAβETA, the patient<br />
Beta-blockers T<br />
should be observed closely for<br />
Chloramphenicol T<br />
hypoglycemia. When these drugs<br />
Clarithromycin C<br />
are withdrawn from a patient<br />
Coumarin derivatives T<br />
receiving DIAβETA, the patient<br />
Cyclophosphamide T<br />
should be observed closely for<br />
Disopyramide T<br />
loss of glycemic control.<br />
Fenfluramine T<br />
Fibrates<br />
T<br />
Fluconazole<br />
T<br />
Fluoxetine<br />
T<br />
Guanethidine T<br />
Ifosfamide<br />
T<br />
Miconazole<br />
T<br />
Monoamine oxidase T<br />
inhibitors<br />
Nonsteroidal antiinflammatory<br />
T<br />
drugs<br />
Oxyphenbutazone T<br />
Para-aminosalicylic T<br />
acid<br />
Pentoxifylline (high T<br />
dose parenteral)<br />
Phenylbutazone T<br />
Probenecid<br />
T<br />
Propranolol<br />
T<br />
Quinolones<br />
T<br />
Salicylates<br />
T<br />
Sulfonamides (e.g T<br />
sulphaphenazole)<br />
Sulphinpyrazone T<br />
Sympatholytic agents T<br />
(e.g. beta-blockers,<br />
guanethidine)<br />
Tetracyclines T<br />
Tuberculostatics T<br />
Page 11 of 26
Table 2. Drugs that may produce hyperglycemia and lead to loss of blood sugar control<br />
Reference Effect<br />
Proper name<br />
Acetazolamide T These drugs tend to produce<br />
Barbiturates<br />
T<br />
hyperglycemia and may lead<br />
Corticosteroids T<br />
to loss of blood sugar control<br />
Diazoxide<br />
T<br />
Diuretics (thiazides, T<br />
furosemide)<br />
Epinephrine and other T<br />
sympathomimetic<br />
agents<br />
Estrogen and<br />
T<br />
progestogen<br />
Glucagon<br />
T<br />
Clinical comment<br />
When these drugs are<br />
administered to a patient<br />
receiving DIAβETA, the patient<br />
should be observed closely for<br />
loss of glycemic control. When<br />
these drugs are withdrawn from a<br />
patient receiving DIAβETA, the<br />
patient should be observed<br />
closely for hypoglycemia.<br />
Isoniazid<br />
Laxatives (after<br />
protracted use)<br />
Nicotinic acid (in<br />
pharmacologic doses)<br />
Phenothiazines<br />
Phenytoin<br />
Rifampicin<br />
Thyroid <strong>product</strong>s<br />
T<br />
T<br />
T<br />
T<br />
T<br />
T<br />
T<br />
Table 3. Other drugs that may interact with DIAβETA<br />
Proper name Reference Effect Clinical comment<br />
Beta-blockers<br />
T<br />
Concurrent use with<br />
(see also table1)<br />
DIAβETA may lead to either<br />
a potentiation or an<br />
attenuation of the bloodglucose-lowering<br />
effect<br />
The signs of adrenergic<br />
counter-regulation to<br />
hypoglycemia may be<br />
reduced or absent in case of<br />
concomitant use with<br />
DIAβETA.<br />
Bosentan C An increased incidence of<br />
elevated liver enzymes was<br />
observed in patients<br />
receiving DIAβETA<br />
concomitantly with bosentan.<br />
Both DIAβETA and<br />
This combination should not be<br />
used.<br />
Page 12 of 26
osentan inhibit the bile salt<br />
export pump, leading to<br />
intracellular accumulation of<br />
cytotoxic bile salts.<br />
Barbiturates T Prolonged barbiturate action To be used cautiously in<br />
patients receiving an oral<br />
hypoglycemic agent.<br />
Clonidine T Concurrent use with<br />
DIAβETA may lead to either<br />
a potentiation or an<br />
attenuation of the bloodglucose-lowering<br />
effect<br />
The signs of adrenergic<br />
counter-regulation to<br />
hypoglycemia may be<br />
reduced or absent in case of<br />
concomitant use with<br />
DIAβETA.<br />
Colesevelam C Colesevelam binds to<br />
DIAβETA and reduces<br />
DIAβETA absorption from<br />
the gastrointestinal track<br />
Coumarin derivatives T DIAβETA may potentiate or<br />
weaken the effects of<br />
coumarin derivatives.<br />
Cyclosporine C DIAβETA may increase<br />
cyclosporine plasma level,<br />
with potentially increased<br />
toxicity.<br />
Drugs containing<br />
alcohol<br />
(see also Drug-<br />
Lifestyle<br />
Interactions<br />
below)<br />
C<br />
Both acute and chronic<br />
alcohol intake may potentiate<br />
or weaken the bloodglucose-lowering<br />
action of<br />
DIAβETA in an<br />
unpredictable fashion.<br />
Guanethidine T The signs of adrenergic<br />
counter-regulation to<br />
hypoglycemia may be<br />
reduced or absent in case of<br />
concomitant use with<br />
No interaction was observed<br />
when DIAβETA was taken at<br />
least 4 hours before<br />
colesevelam. Therefore,<br />
DIAβETA should be<br />
administered at least 4 hours<br />
prior to colesevelam.<br />
Monitoring and dosage<br />
adjustment of cyclosporin are<br />
recommended when both drug<br />
are coadministered.<br />
Intolerance to alcohol<br />
(disulfiram-like reaction;<br />
flushing, sensation of warmth,<br />
giddiness, nausea, and<br />
occasionally tachycardia) may<br />
occur in patients treated with<br />
oral hypoglycemic drugs.<br />
Caution should be exercised<br />
with the concomitant use of<br />
alcohol-containing drugs.<br />
Page 13 of 26
DIAβETA.<br />
H 2 -receptor antagonists T Concurrent use with<br />
DIAβETA may lead to either<br />
a potentiation or an<br />
attenuation of the bloodglucose-lowering<br />
effect<br />
Reserpine T Concurrent use with<br />
DIAβETA may lead to either<br />
a potentiation or an<br />
attenuation of the bloodglucose-lowering<br />
effect<br />
Sympatholytic drugs<br />
(such as beta-blockers,<br />
clonidine, guanethidine,<br />
and reserpine)<br />
T<br />
Legend: C = case study; CT = Clinical Trial; T = Theoretical<br />
The signs of adrenergic<br />
counter-regulation to<br />
hypoglycemia may be<br />
reduced or absent in case of<br />
concomitant use with<br />
DIAβETA<br />
The signs of adrenergic<br />
counter-regulation to<br />
hypoglycemia may be<br />
reduced or absent in case of<br />
concomitant use with<br />
DIAβETA.<br />
In addition, the hypoglycemic action of sulfonylureas is potentiated when used with insulin and<br />
other oral antidiabetics, which is not indicated.<br />
Drug-Food Interactions<br />
Interactions with food have not been established.<br />
Drug-Herb Interactions<br />
Interactions with herbal <strong>product</strong>s have not been established.<br />
Drug-Laboratory Tests Interactions<br />
Interactions with laboratory tests have not been established.<br />
Drug-Lifestyle Interactions<br />
Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when<br />
beginning or after altering treatment, or when DIAβETA is not taken regularly. This may,<br />
for example, affect the ability to drive or to operate machinery.<br />
Page 14 of 26
DOSAGE AND ADMINISTRATION<br />
Dosing Considerations<br />
In diabetic subjects, there is no fixed dosage regimen for management of blood glucose levels.<br />
Individual determination of the minimum dose that will lower the blood glucose adequately<br />
should be made, aiming for glycemic targets as close to normal as possible and, in most people,<br />
as early as possible.<br />
Over a period of time, patients may become progressively less responsive to therapy with oral<br />
hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be<br />
monitored with regular clinical and laboratory evaluations, including blood glucose and<br />
glycosylated hemoglobin (A1 C ) measurements, to determine the minimum effective dosage and<br />
to detect primary failure or secondary failure (see WARNINGS AND PRECAUTIONS).<br />
Adjustment of glyburide dosage should be considered whenever factors predisposing the patient<br />
to the development of hypo- or hyperglycemia, such as illness, weight or life-style changes, are<br />
present (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE<br />
REACTIONS). As an improvement in control of diabetes is, in itself, associated with higher<br />
insulin sensitivity, DIAβETA requirements may fall as treatment proceeds. To avoid<br />
hypoglycemia, timely dose reduction or cessation of DIAβETA therapy must therefore be<br />
considered.<br />
Based on published literature, genetic polymorphisms of CYP2C9 may be associated with an<br />
increased response to DIAβETA. A lower dose regimen in poor metaboliser (CYP2C9*3 variant)<br />
should be considered, however an appropriate dose regimen for this patient population has not<br />
been established in clinical outcome trials (see ACTION AND CLINICAL PHARMACOLOGY,<br />
Pharmacokinetics).<br />
Recommended Dose and Dosage Adjustment<br />
Newly-Diagnosed Diabetics<br />
The initial dose is 5 mg daily (2.5 mg in patients over 60 years of age) administered with<br />
breakfast or a first meal and should be continued for 5 to 7 days. Depending on the response, the<br />
dosage should then be either increased or decreased by steps of 2.5 mg. The maximum daily dose<br />
of DIAβETA is 20 mg (higher doses normally have no additional effect on control of metabolic<br />
state). Occasionally, control is maintained with 2.5 mg daily. The majority of cases can be<br />
controlled by 5 to 10 mg (1 to 2 tablets) daily given as a single dose during or immediately after<br />
breakfast. Patients who eat only a light breakfast should defer the first dose of the day until<br />
lunchtime. If more than 10 mg (2 tablets) daily is required, the excess should be taken with the<br />
evening meal. It is very important not to skip meals after the tablets have been taken.<br />
Changeover from Other Oral Hypoglycemic Agents<br />
There is no exact dosage relationship between DIAβETA and other oral antidiabetic agents.<br />
Discontinue previous oral medication and start DIAβETA 5 mg daily (2.5 mg in patients over 60<br />
Page 15 of 26
years of age). This also applies to patients changed over from the maximum dose of other oral<br />
antidiabetic medication. Determine maintenance dosage as in newly diagnosed diabetics.<br />
Consideration must be given to the potency and duration of action of the previous antidiabetic<br />
agent. A break from medication may be required to avoid any summation of effects entailing a<br />
risk of hypoglycemia.<br />
Changeover from Insulin<br />
If a change from insulin to DIAβETA is contemplated in a patient with stable, mild, Type 2<br />
diabetes, treatment with insulin should be discontinued for a period of two or three days to<br />
determine whether any therapy other than dietary regulation and exercise is needed. During this<br />
insulin-free interval, the patient's urine should be tested at least three times daily for glucose and<br />
ketone-bodies, and the results monitored carefully by a physician. The appearance of significant<br />
ketonuria accompanied by glucosuria within 12 - 24 hours after the withdrawal of insulin<br />
strongly suggests that the patient is ketosis-prone and precludes the change from insulin to<br />
DIAβETA.<br />
Missed Dose<br />
The missed dose should be taken as soon as possible, unless it is almost time for the next dose.<br />
Mistakes, e.g. forgetting to take a dose, must never be corrected by subsequently taking a larger<br />
dose.<br />
Measures for dealing with such mistakes (in particular forgetting a dose or skipping a meal) or in<br />
the event a dose cannot be taken at the prescribed time must be discussed and agreed between<br />
physician and patient beforehand.<br />
If it is discovered that too high a dose or an extra dose of DIAβETA has been taken, a physician<br />
must be notified immediately.<br />
OVERDOSAGE<br />
Overdosage of sulfonylureas, including DIAβETA, can produce hypoglycemia. Mild<br />
hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated<br />
with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should<br />
continue until the physician is assured that the patient is out of danger. Severe hypoglycemic<br />
reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute<br />
medical emergencies requiring immediate hospitalization. In case of overdosage, current medical<br />
intervention for the treatment of hypoglycemia should be followed according to the condition of<br />
the patient. Patients should be closely monitored for a minimum of 24 hours, because<br />
hypoglycemia may recur after apparent clinical recovery.<br />
For management of a suspected drug overdose, contact your regional Poison Control Centre.<br />
Page 16 of 26
ACTION AND CLINICAL PHARMACOLOGY<br />
Mechanism of Action<br />
DIAβETA appears to lower the blood glucose acutely by stimulating the release of insulin from<br />
the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The<br />
mechanism by which DIAβETA lowers blood glucose during long-term administration has not<br />
been clearly established.<br />
With chronic administration in Type II diabetic patients, the blood glucose lowering effect<br />
persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic<br />
effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. In<br />
addition to its blood glucose lowering actions, DIAβETA produces a mild diuresis by<br />
enhancement of renal free water clearance. Clinical experience to date indicates an extremely<br />
low incidence of disulfiram-like reactions in patients while taking DIAβETA.<br />
Pharmacokinetics<br />
Single-dose studies with DIAβETA in normal subjects demonstrate significant absorption within<br />
one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours.<br />
Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve,<br />
increase in proportion to corresponding increases in dose. Multiple-dose studies with DIAβETA<br />
in diabetic patients demonstrate drug level concentration-time curves similar to single dose<br />
studies, indicating no build-up of drug in tissue depots. The decrease of glyburide in the serum of<br />
normal healthy individuals is biphasic, the terminal half-life being about 10 hours. In single-dose<br />
studies in fasting normal subjects, the degree and duration of blood glucose lowering is<br />
proportional to the dose administered and to the area under the drug level concentration-time<br />
curve. The blood glucose lowering effect persists for 24 hours following single morning doses in<br />
non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients,<br />
however, there is no reliable correlation between blood drug levels and fasting blood glucose<br />
levels. A one-year study of diabetic patients treated with DIAβETA showed no reliable<br />
correlation between administered dose and serum drug level.<br />
DIAβETA is eliminated by extensive metabolism in liver. Currently available information from<br />
published in vitro and in vivo pharmacokinetics studies suggest that DIAβETA is mainly<br />
metabolized by CYP2C9 and by CYP3A4. This should be taken into account when DIAβETA is<br />
coadministered with inducers or inhibitors of CYP2C9 and CYP3A4 to avoid potential drug-drug<br />
interactions (see DRUG INTERACTIONS). Genetic polymorphisms may reduce the metabolic<br />
capability of 2C9. Some clinical studies in a limited number of subjects have shown that genetic<br />
polymorphisms of CYP2C9 affect the pharmacokinetics of DIAβETA and that the carriers of<br />
CYP2C9*3 variant (3-8.5% of Caucasians) have lower (30-57%) oral clearance and 1 to 3-fold<br />
higher exposure (AUC (0-∞) ) of DIAβETA. Individuals expressing this variant genotype may<br />
therefore be predisposed to have an increased response to DIABETA. Moreover, the CYP2C9<br />
*3/*3 and *2/*3 genotypes may have an increased risk of hypoglycemia.<br />
The major metabolite of DIAβETA is the 4-trans-hydroxy derivative. A second metabolite, the 3-<br />
cis-hydroxy derivative, also occurs. These metabolites contribute no significant hypoglycemic<br />
Page 17 of 26
action since they are only weakly active (1/400th and 1/40th, respectively, as glyburide) in<br />
rabbits.<br />
DIAβETA is excreted as metabolites in the bile and urine, approximately 50% by each route.<br />
This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are<br />
excreted primarily in the urine.<br />
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding<br />
sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding<br />
exhibited by DIAβETA is predominantly non-ionic, whereas that of other sulfonylureas<br />
(chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as<br />
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum<br />
proteins to a far greater extent than the non-ionic binding DIAβETA. It has not been shown that<br />
this difference in protein binding will result in fewer drug-drug interactions with DIAβETA in<br />
clinical use.<br />
STORAGE AND STABILITY<br />
DIAβETA should be stored between 15 and 30ºC, and not beyond the expiry date indicated on<br />
the package.<br />
DOSAGE FORMS, COMPOSITION AND PACKAGING<br />
DIAβETA (glyburide) 2.5 mg contains 2.5 mg glyburide. DIAβETA (glyburide) 5.0 mg contains<br />
5.0 mg glyburide. Each tablet also contains as non-medicinal ingredients: colloidal anhydrous<br />
silica, lactose monohydrate, magnesium stearate, starch (corn starch and pre-gelatinized corn<br />
starch) and talc.<br />
DIAβETA (glyburide) 2.5 mg tablets are compressed white, flat round beveled tablets with code<br />
letter "LB" above and "G" below the breakline on one side and plain on the other. Available in<br />
cartons of 30 (2 x 15 blister pack).<br />
DIAβETA (glyburide) 5.0 mg tablets are white, biplane, oblong tablets with a score line on both<br />
sides, "LDI" is engraved on each side of the score-line and inverted. The other face is plain.<br />
Available in cartons of 30 (2 x 15 blister pack) or HDPE bottles of 300 tablets.<br />
Page 18 of 26
PART II: SCIENTIFIC INFORMATION<br />
PHARMACEUTICAL INFORMATION<br />
Drug Substance<br />
Proper name:<br />
Chemical name:<br />
Molecular formula:<br />
Glyburide (as per USP)¸ Glibenclamide (as per Ph. Eur.)<br />
1-[[4-[2-[(5-Chloro-2-<br />
methoxybenzoyl)amino]ethyl]phenyl]sulphonyl]-3-cyclohexylurea<br />
C 23 H 28 ClN 3 0 5 S<br />
Molecular mass: 494<br />
Structural formula:<br />
Physicochemical properties:<br />
White or almost white, crystalline powder. Practically<br />
insoluble in water, sparingly soluble in methylene chloride,<br />
slightly soluble in alcohol and in methanol, with a melting<br />
range of 169 – 174 °C.<br />
Page 19 of 26
CLINICAL TRIALS<br />
No clinical data available.<br />
DETAILED PHARMACOLOGY<br />
Animal<br />
In the isolated, perfused rat pancreas, glyburide produced a sustained rise in insulin output. In the<br />
presence of 0.5 mcg/mL of glyburide, isolated rat pancreatic islets released insulin continuously 3 .<br />
When isolated pieces of rat pancreas were repeatedly exposed to glucose or glyburide for brief<br />
periods of time at intervals of 30 minutes, they consistently released insulin 3 . In the presence of<br />
300 mg% of glucose, glyburide (2.5 mcg/min) increased effectively insulin output from isolated<br />
rat pancreas 3,4 .<br />
Sirek et al. 13 found that the beta adrenergic blocker propranolol inhibits sulfonylurea-stimulated<br />
insulin secretion in the dog and that the hypoglycemia produced by glyburide in the presence of<br />
propranolol could be the result of extra-pancreatic effects.<br />
TOXICOLOGY<br />
The LD 50 for white mice, rats and guinea pigs was found to be more than 15 g/kg body weight<br />
and for rabbits and beagles, more than 10 g/kg body weight when glyburide is given orally. The<br />
LD 50 in rats following intraperitoneal injection is 6.3 to 8.4 g/kg body weight.<br />
Long-term feeding experiments were carried out in rats and dogs over the course of one year.<br />
Rats were given glyburide in their food in doses of approximately 0.2, 1.0 and 5.0 mg/kg body<br />
weight daily. The highest dose is equivalent to 350 times the minimal hypoglycemic dose in<br />
man. Organ function tests were carried out continuously. Hematological examination, blood<br />
sugar tests and urinary analyses were performed every three months. None of the rats showed<br />
any abnormal findings in the function tests or the blood and urine studies. Subsequent<br />
post-mortem examination revealed no macroscopic or histological changes attributable to a toxic<br />
effect of glyburide.<br />
Dogs were given glyburide by mouth at dose levels of 0.4, 2.0 and 10.0 mg/kg body weight<br />
daily. The highest dose is equivalent to 650 times the minimal effective hypoglycemic dose in<br />
man. Regular checks of blood cell counts, blood glucose, urine, electrolytes, electrophoresis,<br />
BUN and serum enzyme levels (GPT, GOT, LDH, AP) showed no abnormalities. All the animals<br />
behaved normally during the period of the experiment. There was no vomiting or diarrhea, and<br />
their weights remained unchanged. Subsequent post-mortem examination and histological<br />
investigations showed no abnormality.<br />
Teratological tests were carried out in rats and rabbits. Rats were given 0.2, 20 and 2,000 mg/kg<br />
body weight of glyburide from day 7 to 16 of gestation. For rabbits the doses were 0.035, 3.5 and<br />
350 mg/kg given from day 7 to 17 of gestation in a starch suspension by gastric tube.<br />
Page 20 of 26
Examination of the intact fetuses, followed by examination of transverse sections and of the<br />
stained skeleton, showed no evidence of teratogenic action.<br />
Page 21 of 26
REFERENCES<br />
1. Blant L, Fabre J, Zahno GR. Comparison of the pharmacokinetics of Glipizide in Glipizide<br />
in Glibenclamide in man. Europ J Clin Pharmacol 1975;9:63-69.<br />
2. Falko JM, Osei K. Combination insulin/glyburide therapy in Type II diabetes mellitus.<br />
Effects on lipoprotein metabolism and glucoregulation. The American Journal of<br />
Medicine. 1985 September 20;79 Suppl 3B:92-101.<br />
3. Fucella ML, Tamassia V, Valzelli G. Metabolism and kinetics of the hypoglycemic agent<br />
Glipizide in man - comparison with Glibenclamide. J Clin Pharmacol. 1973;13:68-75.<br />
4. Fussgaenger RD, Goberna R, Hinz M, Jaros P, Karsten C, Pfeiffer EF, Raptis S.<br />
Comparative studies of the dynamics of insulin secretion following HB 419 and<br />
tolbutamide of the perfused isolated rat pancreas and the perfused isolated pieces and islets<br />
of rat pancreas. Hormone and Metabolic Research. 1969;1 Suppl:34.<br />
5. Grodsky GM, Curry D, Landahl H, Bennet L. Further studies on the dynamic aspects of<br />
insulin release in-vitro with evidence of a two-compartmental storage system. Acta<br />
Diabetological Latina 1969;6 Suppl 1:554.<br />
6. Hajdu P, Kohler KF, Schmidt FH, Spingher H. Physikalisch-chemische und analytische<br />
Unter suchungen an HB 419. Arzneim Forsch 1969;19(suppl):1381-1386.<br />
7. Hirn S, Konigstein RP. HB 419, ein neues orales Antidiabetikum und sein Anwendung in<br />
hohen Alter. Weiner Medizinische Wochenschrift 1969;111:632.<br />
8. Karlander SG, Gutniak MKM, Efendic S. Effects of combination therapy with glyburide<br />
and insulin on serum lipid levels in NIDDM patients with secondary sulfonylurea failure.<br />
Diabetes Care. 1991 November;14(11):963-967<br />
9. Mariani MM. The action of sulfonylureas on the insulin secretion of the perfused rat<br />
pancreas. Acta Diabetologica Latina 1969;6 Suppl 1:256.<br />
10. Morris AD, Boyle D, McMahon AD, Pearce H, Evans J, Newton RW. ACE inhibitor use is<br />
associated with hospitalization for severe hypoglycemia in patients with diabetes. Diabetes<br />
Care. 1997 Sept; 20(9): 1363-7.<br />
11. Raptis S, Rau RM, Schroeder KE, Faulhaber JD, Pfeiffer EF. Comparative study of insulin<br />
secretion following repeated administration of Glucose, Tolbutamide and Glibenclamide<br />
(HB 419) in diabetic and non-diabetic human subjects. Hormone and Metabolic Research<br />
1969;1 Suppl:65.<br />
12. Reich A, Abraira C, Lawrence AM. Combined Glyburide and insulin therapy in Type II<br />
diabetes. Diabetes Research 1987; 6: 99-104<br />
Page 22 of 26
13. Rupp W, Christ OE, Fuelberth W. Studies on the bioavailability of Glibenclamide. Arzneim<br />
Forsch 1972;22:47.<br />
14. Rupp W. Bioequivalence study - Glyburide. (Dossier technique, Hoechst Pharmaceuticals,<br />
Département médical, Montréal, Qué.).<br />
15. Rupp W. Dose-response study of the Hoechst formulation of Glyburide. (Dossier<br />
technique, Hoechst Pharmaceuticals, Département médical, Montréal, Qué.).<br />
16. Schulz E, Schmidt FH. Uber den Einfluss von sulfaphenazol, phenylbutazon und<br />
phenprocumarol auf die Elimination von Glibenclamid beim Menschen. Verhandlunen<br />
deutsche Geselschaft fur innue Medizin 1970;76:435.<br />
17. Sirek OV, Sirek A et Policova Z. Inhibition of sulphonylurea-stimulated insulin in secretion<br />
by beta adrenergic blockade. Diabetologia 1975;II(4):269.<br />
18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with<br />
sulphonylureas or insulin compared with conventional treatment and risk of complications<br />
in patients with Type 2 diabetes (UKPDS 33). The Lancet. 1998;352:837-853.<br />
Page 23 of 26
IMPORTANT: PLEASE READ<br />
PART III: CONSUMER INFORMATION<br />
DIAβETA ®<br />
Glyburide Tablets<br />
This leaflet is part III of a three-part “Product Monograph"<br />
published when DIAβETA was approved for sale in <strong>Canada</strong><br />
and is designed specifically for Consumers. This leaflet is a<br />
summary and will not tell you everything about DIAβETA.<br />
Contact your doctor or pharmacist if you have any<br />
questions about the drug.<br />
ABOUT THIS MEDICATION<br />
What the medication is used for:<br />
DIAβETA (glyburide) is used as an adjunct to proper diet,<br />
exercise and weight reduction to lower blood glucose in adult<br />
patients with type 2 diabetes mellitus.<br />
What it does:<br />
DIAβETA lowers blood sugar by stimulating the pancreas to<br />
secrete insulin. The pancreas must produce insulin for this<br />
medication to work.<br />
People with type 2 diabetes are not able to make enough insulin<br />
or respond normally to the insulin their bodies make. When this<br />
happens, sugar (glucose) builds up in the blood. This can lead to<br />
serious medical problems including kidney damage,<br />
amputations, and blindness. Diabetes is also closely linked to<br />
heart disease. The main goal of treating diabetes is to lower<br />
your blood sugar to a normal level and by doing so can prevent<br />
long term complications.<br />
In addition to taking DIAβETA, you should continue to exercise<br />
and follow the diet recommended for you by your doctor.<br />
When it should not be used:<br />
Do not take DIAβETA<br />
If you have Type 1 diabetes.<br />
If you have known hypersensitivity or allergy to this drug,<br />
any sulfonylurea or sulfonamides, or to any ingredient in<br />
the formulation or component of the container.<br />
If you have diabetic ketoacidosis (an emergency condition<br />
with high blood glucose levels, a lack of insulin and an<br />
accumulation of ketones (chemicals) in the blood and<br />
urine). This condition should be treated with insulin.<br />
Diabetic precoma or coma.<br />
During stress conditions such as severe infections, trauma<br />
or surgery.<br />
In the presence of liver disease or frank jaundice; or kidney<br />
disease.<br />
If you are being treated with bosentan.<br />
If you are pregnant or breastfeeding.<br />
What the medicinal ingredient is:<br />
The medicinal ingredient for DIAβETA is glyburide.<br />
What the important nonmedicinal ingredients are:<br />
DIAβETA tablets contain the following non-medicinal<br />
ingredients: colloidal anhydrous silica, lactose monohydrate,<br />
magnesium stearate, starch (corn starch and pre-gelatinized<br />
corn starch) and talc.<br />
What dosage forms it comes in:<br />
Tablets. Each tablet contains 2.5 mg or 5.0 mg glyburide.<br />
WARNINGS AND PRECAUTIONS<br />
Proper diet, exercise and weight reduction are important to<br />
help you control your diabetes.<br />
Your blood glucose may change in some situations, for<br />
example if you are stressed or suffering from other illnesses<br />
(e.g. infections). At such times, your doctor may need to<br />
modify your dose.<br />
DIAβETA may cause low blood sugar (hypoglycemia),<br />
especially if you miss a meal, exercise for a long time, drink<br />
alcohol or use another antidiabetic medication with<br />
DIAβETA.<br />
If your blood sugar gets too low, you may feel shaky, weak,<br />
drowsy, confused, or very hungry. You may sweat or have<br />
blurred vision, abnormal heartbeats, trouble concentrating,<br />
or a headache that doesn't go away. Signs of severe<br />
hypoglycemia can include disorientation, loss of<br />
consciousness, and seizures.<br />
You should ask your doctor, pharmacist or diabetes educator<br />
about symptoms of low blood sugar and what to do if you<br />
experience these symptoms. Teach your friends, co-workers,<br />
or family members what they can do to help you if you have<br />
low blood sugar.<br />
You should also test your blood sugar as instructed by your<br />
doctor.<br />
Before you use DIAβETA talk to your doctor or pharmacist<br />
if:<br />
You have or have had liver, kidney, or heart disease;<br />
You are pregnant or planning to get pregnant;<br />
You are breast-feeding.<br />
You have a blood disease called G6PD-deficiency<br />
anemia<br />
DIAβETA is not recommended for use in children under 18<br />
years of age.<br />
Page 24 of 26
IMPORTANT: PLEASE READ<br />
Driving and Operating Machinery:<br />
Alertness and reactions may be impaired due to low or high<br />
blood sugar (hypo- or hyperglycemia), especially when<br />
beginning or after changing treatment or when DIAβETA is not<br />
taken regularly. This may affect your ability to drive or to<br />
operate machinery.<br />
INTERACTIONS WITH THIS MEDICATION<br />
Ask your doctor or pharmacist before taking any other<br />
medicine, including over-the-counter <strong>product</strong>s.<br />
Drugs that can interact with DIAβETA include: diuretics (water<br />
pills), corticosteroids (such as prednisone), ACE inhibitors (a<br />
drug used to treat high blood pressure (hypertension)), birth<br />
control pills, and some kinds of cold and allergy drugs.<br />
Avoid drinking alcohol while you are taking DIAβETA.<br />
PROPER USE OF THIS MEDICATION<br />
Usual dose:<br />
Take DIAβETA exactly as prescribed by your doctor.<br />
The usual dose is 2.5 to 10 mg daily. Maximum daily dose is 20<br />
mg.<br />
A dose of more than 10 mg should be taken in two divided<br />
doses.<br />
Tablets should be taken during or immediately after meals.<br />
Overdose:<br />
Overdosage with this medication may result in hypoglycemia.<br />
In case of drug overdose, contact a health professional,<br />
hospital emergency department or regional Poison Control<br />
Centre immediately, even if there are no symptoms.<br />
Missed Dose:<br />
If you forget to take DIAβETA tablets, do not take a double<br />
dose to make up for forgotten individual doses.<br />
Discuss with your healthcare for dealing with such mistakes (in<br />
particular forgetting a dose or skipping a meal) or in the event a<br />
dose cannot be taken at the prescribed time.<br />
SIDE EFFECTS AND WHAT TO DO ABOUT<br />
THEM<br />
Side effects:<br />
As with any type of medication, DIAβETA is associated with<br />
some side effects.<br />
The most common side effect of DIAβETA is low blood<br />
sugar (hypoglycemia). Please see the WARNINGS and<br />
PRECAUTIONS section above.<br />
The following side effects have been observed with<br />
DIAβETA use: nausea, heartburn, feeling “full”, vomiting,<br />
diarrhea and abdominal pain.<br />
Allergic skin reactions (itchiness, rash, eruption) have been<br />
reported in a number of patients. An increased sensibility to<br />
light has been associated with the use of oral antidiabetic<br />
drugs.<br />
Transient visual disturbances may occur at the beginning of<br />
the treatment due to variations in level of blood sugar.<br />
SERIOUS SIDE EFFECTS, HOW OFTEN THEY<br />
HAPPEN AND WHAT TO DO ABOUT THEM<br />
Symptom/<br />
Effect<br />
Common<br />
Uncommon<br />
Rare<br />
Very rare<br />
Low blood<br />
sugar<br />
(hypoglycemia)<br />
Skin reactions<br />
(itchiness, rash,<br />
eruption)<br />
Blood<br />
disorders<br />
(unusual<br />
bruising or<br />
bleeding)<br />
Liver problem<br />
(yellowing of<br />
the eyes or<br />
skin)<br />
Allergic<br />
reaction<br />
(difficult<br />
breathing,<br />
decreased<br />
blood pressure)<br />
Talk with<br />
your doctor<br />
or pharmacist<br />
Only<br />
if<br />
severe<br />
√<br />
In<br />
all<br />
cases<br />
√<br />
√<br />
Stop taking<br />
DIAβETA<br />
and call<br />
your doctor<br />
or<br />
pharmacist<br />
This is not a complete list of side effects. For any<br />
unexpected effects while taking DIAβETA, contact your<br />
doctor or pharmacist.<br />
√<br />
√<br />
Page 25 of 26
IMPORTANT: PLEASE READ<br />
HOW TO STORE IT<br />
DIAβETA should be stored between 15-30°C, and not beyond<br />
the expiry date indicated on the package.<br />
REPORTING SUSPECTED SIDE EFFECTS<br />
You can report any suspected adverse reactions<br />
associated with the use of health <strong>product</strong>s to the<br />
<strong>Canada</strong> Vigilance Program by one of the following 3<br />
ways:<br />
Report online at:<br />
www.healthcanada.gc.ca/medeffect<br />
Call toll-free at 1-866-234-2345<br />
Complete a <strong>Canada</strong> Vigilance Reporting Form<br />
and:<br />
- Fax toll-free to 1-866-678-6789, or<br />
- Mail to:<br />
<strong>Canada</strong> Vigilance Program<br />
Health <strong>Canada</strong><br />
Postal Locator 0701E<br />
Ottawa, ON K1A 0K9<br />
Postage paid labels, <strong>Canada</strong> Vigilance Reporting<br />
Form and the adverse reaction reporting guidelines<br />
are available on the MedEffect <strong>Canada</strong> Web site at<br />
www.healthcanada.gc.ca/medeffect.<br />
NOTE: Should you require information related to the<br />
management of side effects, contact your health<br />
professional. The <strong>Canada</strong> Vigilance Program does<br />
not provide medical advice.<br />
MORE INFORMATION<br />
This document plus the full <strong>product</strong> <strong>monograph</strong>, prepared for<br />
health professionals can be found by contacting the sponsor,<br />
sanofi-aventis <strong>Canada</strong> Inc., at: at: 1-800-265-7927 or at<br />
www.sanofi.ca<br />
This leaflet was prepared by sanofi-aventis <strong>Canada</strong> Inc.<br />
Last revised: March 12, 2013<br />
Page 26 of 26